Aim To examine the clinical effect of four antidementia drugs (donepezil, galantamine, rivastigmine and memantine) in Alzheimer's disease patients who were divided into subgroups based on their periventricular hyperintensity (PVH) severity. Methods A total of 551 Alzheimer's disease patients (201 men and 350 women) were divided into four subgroups based on their PVH severity (0–III). They received monotherapy for 12 months. We compared the clinical effects at the baseline, and at 3, 6 and 12 months after initiation. Results The baseline age became higher with PVH grades, and the Mini‐Mental State Examination and Hasegawa Dementia Scale‐Revised showed a decrease that was dependent on white matter severity. Although the PVH 0 subgroup showed stable cognitive, affective and ADL functions until 12 months in all four drug groups, the PVH I subgroup showed an improved Apathy Scale from the baseline in response to memantine at 3 and 9 months (P < 0.05), and galantamine at 9 months (P < 0.01). In the PVH II subgroup, the Mini‐Mental State Examination showed a significant improvement from the baseline in response to galantamine (P < 0.05) at 9 months and Hasegawa Dementia Scale‐Revised (P < 0.05) at 3 months. In the PVH III subgroup, cognitive and affective functions were preserved in all four drug groups until 12 months, but activities of daily living deteriorated in the riverstigmine group at 6 and 12 months (P < 0.05). Conclusions The present study shows that these four drugs showed sensitivity dependent on white matter severity that clinically affected cognitive, affective and activities of daily living functions. Geriatr Gerontol Int 2017; ••: ••–••.